Interaction of the protein tyrosine phosphatase PTPL1 with the PtdIns(3,4)P2-binding adaptor protein TAPP1

Abstract

It has been postulated that PtdIns(3,4) P (2), one of the immediate breakdown products of PtdIns(3,4,5) P (3), functions as a signalling molecule in insulin- and growth-factor-stimulated pathways. To date, the t andem- P H-domain-containing p rotein- 1 (TAPP1) and related TAPP2 are still the only known PH-domain-containing proteins that interact strongly and specifically with PtdIns(3,4) P (2). In this study we demonstrate that endogenously expressed TAPP1, is constitutively associated with the protein-tyrosine-phosphatase-like protein-1 (PTPL1 also known as FAP-1). We show that PTPL1 binds to TAPP1 and TAPP2, principally though its first PDZ domain [where PDZ is postsynaptic density protein ( P SD-95)/ Drosophila disc large tumour suppressor ( d lg)/tight junction protein ( Z O1)] and show that this renders PTPL1 capable of associating with PtdIns(3,4) P (2) in vitro. Our data suggest that the binding of TAPP1 to PTPL1 does not influence PTPL1 phosphatase activity, but instead functions to maintain PTPL1 in the cytoplasm. Following stimulation of cells with hydrogen peroxide to induce PtdIns(3,4) P (2) production, PTPL1, complexed to TAPP1, translocates to the plasma membrane. This study provides the first evidence that TAPP1 and PtdIns(3,4) P (2) could function to regulate the membrane localization of PTPL1. We speculate that if PTPL1 was recruited to the plasma membrane by increasing levels of PtdIns(3,4) P (2), it could trigger a negative feedback loop in which phosphoinositide-3-kinase-dependent or other signalling pathways could be switched off by the phosphatase-catalysed dephosphorylation of receptor tyrosine kinases or tyrosine phosphorylated adaptor proteins such as IRS1 or IRS2. Consistent with this notion we observed RNA-interference-mediated knock-down of TAPP1 in HEK-293 cells, enhanced activation and phosphorylation of PKB following IGF1 stimulation.

Crystal Structure of the PTPL1/FAP-1 Human Tyrosine Phosphatase Mutated in Colorectal Cancer

“…The findings that PTPL1 is associated with the plasma membrane through its FERM domain (37) and that the cytosolic PTPL1-TAPP1 complex can translocate to the plasma membrane in response to agonists that generate PtdIns(3,4)P 2 (4) also support the notion that PTPL1 could down-regulate insulin growth factor-mediated signaling processes. As (PtdIns(3,4)P 2 ) is generated as a breakdown product of phosphatidylinositol (3,4,5)trisphosphate (PtdIns(3,4,5)P 3 ), the TAPP1-mediated recruitment of PTPL1 to the plasma membrane could serve as a simple mechanism to switch off PI 3-kinase signaling pathways.…”

“…This was first based on the finding that overexpression of PTPL1 in a breast cancer cell line induced the dephosphorylation of the insulin receptor substrate protein-1 (IRS1), resulting in inhibition of PI 3-kinase-regulated cell growth and survival responses (5). Subsequently, the cellular localization of PTPL1 was also found to be controlled by PI 3-kinase, through a PDZ domain-mediated interaction of PTPL1 with the phosphatidylinositol 3,4 bisphosphate (PtdIns(3,4)P 2 ) binding adaptor protein, TAPP1 (4). Binding of TAPP1 to PTPL1 localizes PTPL1 in the cytosol, and following stimulation of cells with agonists, which elevate the level of PtdIns(3,4)P 2 , PTPL1 is recruited to the plasma membrane.…”

“…3). The non-catalytic domain of PTPL1 does not appear to control PTPL1 activity directly as the isolated catalytic domain of PTPL1 possesses the same activity as full-length PTPL1 (4).…”

PTPL1: a large phosphatase with a split personality

“…Endogenous PTPL1 and TAPP1 co-localized predominantly in the cytoplasm, while an H 2 O 2 -stimulated increase of intracellular PIP2 levels led to higher levels of co-localization between endogenous TAPP1 and PTPL1 at the cell membrane [25]. In addition to the TAPP1/2 interactions, PDZ1 has been shown to bind the inhibitor of nuclear factor kappa-B alpha (IκBα) [26] as well as the transient receptor potential (TRP) superfamily member TRPM2 [27].…”

“…The first PTPL1 PDZ domain (PDZ1) binds a family of PIP2-binding adaptor proteins known as tandem-PH-domain-containing proteins 1 and 2 (TAPP1/2) [25]. Endogenous PTPL1 and TAPP1 co-localized predominantly in the cytoplasm, while an H 2 O 2 -stimulated increase of intracellular PIP2 levels led to higher levels of co-localization between endogenous TAPP1 and PTPL1 at the cell membrane [25].…”